Methods for treating a buttock deformity

ABSTRACT

Methods for treating a buttock deformity or for preventing development of a buttock deformity by local administration of a Clostridial toxin, such as a botulinum neurotoxin, to a buttock deformity or to the vicinity of a buttock deformity.

BACKGROUND

The present invention relates to methods for treating a buttockdeformity. In particular, the present invention relates to methods fortreating a buttock deformity by administration of a Clostridialneurotoxin, such as a botulinum toxin, to a patient.

A buttock is a prominence formed in large part by the gluteal muscles.In the normal condition, human have two buttocks located dorsally abovethe thighs and below the back. There are three gluteal muscles, thegluteus maximus, gluteus medius and gluteus minimus muscles. The bulk ofa buttock is formed by the gluteus maximus muscle. The gluteus maximusoriginates from the ilium behind the posterior gluteal line on theposterior surface of the sacrum and coccyx and inserts into theiliotibial band and the gluteal tuberosity of the femur. The gluteusmaximus allows for the extension of the thigh, especially from theflexed position, as in climbing stairs or rising from a sittingposition. The gluteus medius is partly covered by the gluteus maximus.The gluteus medius originates from the ilium between the anterior andposterior gluteal lines and inserts into the lateral surface of thegreater trochanter. The gluteus medius allows for the abduction androtation of the thigh. The gluteus minimus lies beneath the gluteusmedius. The gluteus minimus originates from the ilium between theanterior and inferior gluteal lines and inserts into the greatertrochanter of the femur and it facilitates the gluteus medius in theabduction of the thigh. In the normal buttock, the glutei musculatureforms well rounded and symmetrical buttocks with a horizontal glutealline.

A buttock deformity can include a large or prominent buttock, adeficient or flat buttock, lack of or an uneven buttock crease and fold,a depression in a buttock, a square shaped buttock, an irregularlyshaped or asymmetric buttock or ptosis (sagging) of a buttock. A buttockdeformity can be the result of a birth defect, injury, surgery(including prior cosmetic surgery) or of a perceived or actual cosmeticdeficiency or defect.

Flattening of the upper, outer quadrant of the buttock or a looselyhanging appearance of the buttock suggests weakness of the gluteusmaximus or inhibition of the muscle due to tightness of the hip flexorsor sacroiliac joint dysfunction. In the case of sacroiliac jointdysfunction changes in muscle activation can occur due to arthrogenicinhibition of the gluteus maximus on the side of the blocked joint andof the gluteus medius on the contralateral side. Painful spasms of theiliacus, piriformis and rectos abdominis can also occur.

An injury which results in a buttock defect can begin as a hematoma (ascan result from a fall) which reduces fat levels within the buttockform. Upon drainage or resorbtion of the hematoma a depression canremain. Surgery can result in a buttock contour irregularity.Additionally steroid injections into a fatty portion of a buttock cancause absorption and atrophy of fat cells, which can result a buttockdepression. A buttock deformity can be due to surgery for example fromuse of abdominal liposuction which removes buttock supporting tissue andcan causes ptosis (drooping or sagging) of a buttock.

Cosmetic surgery to a buttock can be for a variety of reasons, such asto alter and thereby enhance a buttock shape (as by use of buttockimplants or by using liposuction to create a different buttock fold andcontour), to reduce a buttock prominence (as through liposuction).Patients can seek liposuction of the buttocks to create a better foldand contour.

Limb length discrepancy is a condition where one leg is longer than theother. When a substantial difference exist disruptive effects on gaitand posture can occur. For a functional limb length discrepancy, relatedto abnormal pronation of the foot, a functional orthotic device tocorrect the pronatory motion may be sufficient. Muscle strengthening andstretching is also an important part of the functional deformitytherapy. For a combination of functional and structural deformity, acombination of lifts and orthotics may be required. Purely structuraldeformities can require lifts.

Botulinum Toxin

The genus Clostridium has more than one hundred and twenty sevenspecies, grouped according to their morphology and functions. Theanaerobic, gram positive bacterium Clostridium botulinum produces apotent polypeptide neurotoxin, botulinum toxin, which causes aneuroparalytic illness in humans and animals referred to as botulism.The spores of Clostridium botulinum are found in soil and can grow inimproperly sterilized and sealed food containers of home basedcanneries, which are the cause of many of the cases of botulism. Theeffects of botulism typically appear 18 to 36 hours after eating thefoodstuffs infected with a Clostridium botulinum culture or spores. Thebotulinum toxin can apparently pass unaftenuated through the lining ofthe gut and shows a high affinity for cholinergic motor neurons.Symptoms of botulinum toxin intoxication can progress from difficultywalking, swallowing, and speaking to paralysis of the respiratorymuscles and death.

Botulinum toxin type A is the most lethal natural biological agent knownto man. About 50 picograms of a commercially available botulinum toxintype A (purified neurotoxin complex)¹ is a LD50 in mice (i.e. 1 unit).One unit of BOTOX® contains about 50 picograms (about 56 attomoles) ofbotulinum toxin type A complex. Interestingly, on a molar basis,botulinum toxin type A is about 1.8 billion times more lethal thandiphtheria, about 600 million times more lethal than sodium cyanide,about 30 million times more lethal than cobra toxin and about 12 milliontimes more lethal than cholera. Singh, Critical Aspects of BacterialProtein Toxins, pages 63-84 (chapter 4) of Natural Toxins II, edited byB. R. Singh et al., Plenum Press, New York (1976) (where the stated LD50of botulinum toxin type A of 0.3 ng equals 1 U is corrected for the factthat about 0.05 ng of BOTOX® equals 1 unit). One unit (U) of botulinumtoxin is defined as the LD50 upon intraperitoneal injection into femaleSwiss Webster mice weighing 18 to 20 grams each.

Seven generally immunologically distinct botulinum neurotoxins have beencharacterized these being respectively botulinum neurotoxin serotypes A,B, C₁, D, E, F and G each of which is distinguished by neutralizationwith type-specific antibodies. The different serotypes of botulinumtoxin vary in the animal species that they affect and in the severityand duration of the paralysis they evoke. For example, it has beendetermined that botulinum toxin type A is 500 times more potent, asmeasured by the rate of paralysis produced in the rat, than is botulinumtoxin type B. Additionally, botulinum toxin type B has been determinedto be non-toxic in primates at a dose of 480 U/kg which is about 12times the primate LD50 for botulinum toxin type A. Moyer E et al.,Botulinum Toxin Type B: Experimental and Clinical Experience, beingchapter 6, pages 71-85 of “Therapy With Botulinum Toxin,” edited byJankovic, J. et al. (1994), Marcel Dekker, Inc. Botulinum toxinapparently binds with high affinity to cholinergic motor neurons, istranslocated into the neuron and blocks the release of acetylcholine.Additional uptake can take place through low affinity receptors, as wellas by phagocytosis and pinocytosis.

Regardless of serotype, the molecular mechanism of toxin intoxicationappears to be similar and to involve at least three steps or stages. Inthe first step of the process, the toxin binds to the presynapticmembrane of the target neuron through a specific interaction between theheavy chain (the H chain or HC), and a cell surface receptor. Thereceptor is thought to be different for each type of botulinum toxin andfor tetanus toxin. The carboxyl end segment of the HC appears to beimportant for targeting of the botulinum toxin to the cell surface.

In the second step, the botulinum toxin crosses the plasma membrane ofthe target cell. The botulinum toxin is first engulfed by the cellthrough receptor-mediated endocytosis, and an endosome containing thebotulinum toxin is formed. The toxin then escapes the endosome into thecytoplasm of the cell. This step is thought to be mediated by the aminoend segment of the HC, the HN, which triggers a conformational change ofthe toxin in response to a pH of about 5.5 or lower. Endosomes are knownto possess a proton pump which decreases intra-endosomal pH. Theconformational shift exposes hydrophobic residues in the toxin, whichpermits the botulinum toxin to embed itself in the endosomal membrane.The botulinum toxin (or at least the light chain of the botulinum) thentranslocates through the endosomal membrane into the cytoplasm.

The last step of the mechanism of botulinum toxin activity appears toinvolve reduction of the disulfide bond joining the heavy chain, Hchain, and the light chain, L chain. The entire toxic activity ofbotulinum andAvailable from Allergan, Inc., of Irvine, Calif. under the tradenameBOTOX® in 100 unit vials) tetanus toxins is contained in the L chain ofthe holotoxin; the L chain is a zinc (Zn++) endopeptidase whichselectively cleaves proteins essential for recognition and docking ofneurotransmitter-containing vesicles with the cytoplasmic surface of theplasma membrane, and fusion of the vesicles with the plasma membrane.Tetanus neurotoxin, botulinum toxin types B, D, F, and G causedegradation of synaptobrevin (also called vesicle-associated membraneprotein (VAMP)), a synaptosomal membrane protein. Most of the VAMPpresent at the cytoplasmic surface of the synaptic vesicle is removed asa result of any one of these cleavage events. Botulinum toxin serotype Aand E cleave SNAP-25. Botulinum toxin serotype C1 was originally thoughtto cleave syntaxin, but was found to cleave syntaxin and SNAP-25. Eachof the botulinum toxins specifically cleaves a different bond, exceptbotulinum toxin type B (and tetanus toxin) which cleave the same bond.Each of these cleavages block the process of vesicle-membrane docking,thereby preventing exocytosis of vesicle content.

Botulinum toxins have been used in clinical settings for the treatmentof neuromuscular disorders characterized by hyperactive skeletal muscles(i.e. motor disorders). In 1989, a botulinum toxin type A complex wasapproved by the U.S. Food and Drug Administration for the treatment ofblepharospasm, strabismus and hemifacial spasm. Subsequently, abotulinum toxin type A was also approved by the FDA for the treatment ofcervical dystonia and for the treatment of glabellar lines, and abotulinum toxin type B was approved for the treatment of cervicaldystonia. Non-type A botulinum toxin serotypes apparently have a lowerpotency and/or a shorter duration of activity as compared to botulinumtoxin type A. Clinical effects of peripheral intramuscular botulinumtoxin type A are usually seen within one week of injection. The typicalduration of symptomatic relief from a single intramuscular injection ofbotulinum toxin type A averages about three months, althoughsignificantly longer periods of therapeutic activity have been reported.

Although all the botulinum toxins serotypes apparently inhibit releaseof the neurotransmitter acetylcholine at the neuromuscular junction,they do so by affecting different neurosecretory proteins and/orcleaving these proteins at different sites. For example, botulinum typesA and E both cleave the 25 kiloDalton (kD) synaptosomal associatedprotein (SNAP-25), but they target different amino acid sequences withinthis protein. Botulinum toxin types B, D, F and G act onvesicle-associated protein (VAMP, also called synaptobrevin), with eachserotype cleaving the protein at a different site. Finally, botulinumtoxin type C1 has been shown to cleave both syntaxin and SNAP-25. Thesedifferences in mechanism of action may affect the relative potencyand/or duration of action of the various botulinum toxin serotypes.Apparently, a substrate for a botulinum toxin can be found in a varietyof different cell types. See e.g. Biochem J 1;339 (pt 1):159-65:1999,and Mov Disord, 10(3):376:1995 (pancreatic islet B cells contains atleast SNAP-25 and synaptobrevin).

The molecular weight of the botulinum toxin protein molecule, for allseven of the known botulinum toxin serotypes, is about 150 kD.Interestingly, the botulinum toxins are released by Clostridialbacterium as complexes comprising the 150 kD botulinum toxin proteinmolecule along with associated non-toxin proteins. Thus, the botulinumtoxin type A complex can be produced by Clostridial bacterium as 900 kD,500 kD and 300 kD forms. Botulinum toxin types B and C1 are apparentlyproduced as only a 700 kD or 500 kD complex. Botulinum toxin type D isproduced as both 300 kD and 500 kD complexes. Finally, botulinum toxintypes E and F are produced as only approximately 300 kD complexes. Thecomplexes (i.e. molecular weight greater than about 150 kD) are believedto contain a non-toxin hemagglutinin proteins and a non-toxin andnon-toxic nonhemagglutinin protein. These two non-toxin proteins (whichalong with the botulinum toxin molecule comprise the relevant neurotoxincomplex) may act to provide stability against denaturation to thebotulinum toxin molecule and protection against digestive acids when abotulinum toxin is ingested. Additionally, it is possible that thelarger (greater than about 150 kD molecular weight) botulinum toxincomplexes may result in a slower rate of diffusion of the botulinumtoxin away from a site of intramuscular injection of a botulinum toxincomplex.

In vitro studies have indicated that botulinum toxin inhibits potassiumcation induced release of both acetylcholine and norepinephrine fromprimary cell cultures of brainstem tissue. Additionally, it has beenreported that botulinum toxin inhibits the evoked release of bothglycine and glutamate in primary cultures of spinal cord neurons andthat in brain synaptosome preparations botulinum toxin inhibits therelease of each of the neurotransmitters acetylcholine, dopamine,norepinephrine (Habermann E., et al., Tetanus Toxin and Botulinum A andC Neurotoxins Inhibit Noradrenaline Release From Cultured Mouse Brain, JNeurochem 51(2);522-527:1988) CGRP, substance P and glutamate(Sanchez-Prieto, J., et al., Botulinum Toxin A Blocks GlutamateExocytosis From Guinea Pig Cerebral Cortical Synaptosomes, Eur J.Biochem 165;675-681:1897. Thus, when adequate concentrations are used,stimulus-evoked release of most neurotransmitters can be blocked bybotulinum toxin. See e.g. Pearce, L. B., Pharmacologic Characterizationof Botulinum Toxin For Basic Science and Medicine, Toxicon35(9);1373-1412 at 1393; Bigalke H., et al., Botulinum A NeurotoxinInhibits Non-Cholinergic Synaptic Transmission in Mouse Spinal CordNeurons in Culture, Brain Research 360;318-324:1985; Habermann E.,Inhibition by Tetanus and Botulinum A Toxin of the release of[3H]Noradrenaline and [3H]GABA From Rat Brain Homogenate, Experientia44;224-226:1988, Bigalke H., et al., Tetanus Toxin and Botulinum A ToxinInhibit Release and Uptake of Various Transmitters, as Studied withParticulate Preparations From Rat Brain and Spinal Cord,Naunyn-Schmiedeberg's Arch Pharmacol 316;244-251:1981, and; Jankovic J.et al., Therapy With Botulinum Toxin, Marcel Dekker, Inc., (1994), page5.

Botulinum toxin type A can be obtained by establishing and growingcultures of Clostridium botulinum in a fermenter and then harvesting andpurifying the fermented mixture in accordance with known procedures. Allthe botulinum toxin serotypes are initially synthesized as inactivesingle chain proteins which must be cleaved or nicked by proteases tobecome neuroactive. The bacterial strains that make botulinum toxinserotypes A and G possess endogenous proteases and serotypes A and G cantherefore be recovered from bacterial cultures in predominantly theiractive form. In contrast, botulinum toxin serotypes C1, D and E aresynthesized by nonproteolytic strains and are therefore typicallyunactivated when recovered from culture. Serotypes B and F are producedby both proteolytic and nonproteolytic strains and therefore can berecovered in either the active or inactive form. However, even theproteolytic strains that produce, for example, the botulinum toxin typeB serotype only cleave a portion of the toxin produced. The exactproportion of nicked to unnicked molecules depends on the length ofincubation and the temperature of the culture. Therefore, a certainpercentage of any preparation of, for example, the botulinum toxin typeB toxin is likely to be inactive, possibly accounting for the knownsignificantly lower potency of botulinum toxin type B as compared tobotulinum toxin type A. The presence of inactive botulinum toxinmolecules in a clinical preparation will contribute to the overallprotein load of the preparation, which has been linked to increasedantigenicity, without contributing to its clinical efficacy.Additionally, it is known that botulinum toxin type B has, uponintramuscular injection, a shorter duration of activity and is also lesspotent than botulinum toxin type A at the same dose level.

High quality crystalline botulinum toxin type A can be produced from theHall A strain of Clostridium botulinum with characteristics of ≧3×107U/mg, an A260/A278 of less than 0.60 and a distinct pattern of bandingon gel electrophoresis. The known Shantz process can be used to obtaincrystalline botulinum toxin type A, as set forth in Shantz, E. J., etal, Properties and use of Botulinum toxin and Other MicrobialNeurotoxins in Medicine, Microbiol Rev. 56;80-99:1992. Generally, thebotulinum toxin type A complex can be isolated and purified from ananaerobic fermentation by cultivating Clostridium botulinum type A in asuitable medium. The known process can also be used, upon separation outof the non-toxin proteins, to obtain pure botulinum toxins, such as forexample: purified botulinum toxin type A with an approximately 150 kDmolecular weight with a specific potency of 1-2×108 LD50 U/mg orgreater; purified botulinum toxin type B with an approximately 156 kDmolecular weight with a specific potency of 1-2×108 LD50 U/mg orgreater, and; purified botulinum toxin type F with an approximately 155kD molecular weight with a specific potency of 1-2×107 LD50 U/mg orgreater.

Botulinum toxins and/or botulinum toxin complexes can be obtained fromList Biological Laboratories, Inc., Campbell, Calif.; the Centre forApplied Microbiology and Research, Porton Down, U.K.; Wako (Osaka,Japan), Metabiologics (Madison, Wis.) as well as from Sigma Chemicals ofSt Louis, Mo. Pure botulinum toxin can also be used to prepare apharmaceutical composition.

As with enzymes generally, the biological activities of the botulinumtoxins (which are intracellular peptidases) are dependant, at least inpart, upon their three dimensional conformation. Thus, botulinum toxintype A is detoxified by heat, various chemicals surface stretching andsurface drying. Additionally, it is known that dilution of a botulinumtoxin complex obtained by the known culturing, fermentation andpurification to the much, much lower toxin concentrations used forpharmaceutical composition formulation results in rapid detoxificationof the toxin unless a suitable stabilizing agent is present. Dilution ofthe toxin from milligram quantities to a solution containing nanogramsper milliliter presents significant difficulties because of the rapidloss of specific toxicity upon such great dilution. Since the botulinumtoxin may be used months or years after the toxin containingpharmaceutical composition is formulated, the toxin can be stabilizedwith a stabilizing agent such as albumin and gelatin.

A commercially available botulinum toxin containing pharmaceuticalcomposition is sold under the trademark BOTOX® (available from Allergan,Inc., of Irvine, Calif.). BOTOX® consists of a purified botulinum toxintype A complex, albumin and sodium chloride packaged in sterile,vacuum-dried form. The botulinum toxin type A is made from a culture ofthe Hall strain of Clostridium botulinum grown in a medium containingN-Z amine and yeast extract. The botulinum toxin type A complex ispurified from the culture solution by a series of acid precipitations toa crystalline complex consisting of the active high molecular weighttoxin protein and an associated hemagglutinin protein. The crystallinecomplex is re-dissolved in a solution containing saline and albumin andsterile filtered (0.2 microns) prior to vacuum-drying. The vacuum-driedproduct is stored in a freezer at or below −5° C. BOTOX® can bereconstituted with sterile, non-preserved saline prior to intramuscularinjection. Each vial of BOTOX® contains about 100 units (U) ofClostridium botulinum toxin type A purified neurotoxin complex, 0.5milligrams of human serum albumin and 0.9 milligrams of sodium chloridein a sterile, vacuum-dried form without a preservative.

To reconstitute vacuum-dried BOTOX®, sterile normal saline without apreservative; (0.9% Sodium Chloride Injection) is used by drawing up theproper amount of diluent in the appropriate size syringe. Since BOTOX®may be denatured by bubbling or similar violent agitation, the diluentis gently injected into the vial. For sterility reasons BOTOX® ispreferably administered within four hours after the vial is removed fromthe freezer and reconstituted. During these four hours, reconstitutedBOTOX® can be stored in a refrigerator at about 2° C. to about 8° C.Reconstituted, refrigerated BOTOX® has been reported to retain itspotency for at least about two weeks. Neurology, 48:249-53:1997.

It has been reported that botulinum toxin type A has been used inclinical settings as follows:

-   (1) about 75-125 units of BOTOX® per intramuscular injection    (multiple muscles) to treat cervical dystonia;-   (2) 5-10 units of BOTOX® per intramuscular injection to treat    glabellar lines (brow furrows) (5 units injected intramuscularly    into the procerus muscle and 10 units injected intramuscularly into    each corrugator supercilii muscle);-   (3) about 30-80 units of BOTOX® to treat constipation by    intrasphincter injection of the puborectalis muscle;-   (4) about 1-5 units per muscle of intramuscularly injected BOTOX® to    treat blepharospasm by injecting the lateral pre-tarsal orbicularis    oculi muscle of the upper lid and the lateral pre-tarsal orbicularis    oculi of the lower lid.-   (5) to treat strabismus, extraocular muscles have been injected    intramuscularly with between about 1-5 units of BOTOX®, the amount    injected varying based upon both the size of the muscle to be    injected and the extent of muscle paralysis desired (i.e. amount of    diopter correction desired).-   (6) to treat upper limb spasticity following stroke by intramuscular    injections of BOTOX® into five different upper limb flexor muscles,    as follows:-   (a) flexor digitorum profundus: 7.5 U to 30 U-   (b) flexor digitorum sublimus: 7.5 U to 30 U-   (c) flexor carpi ulnaris: 10 U to 40 U-   (d) flexor carpi radialis: 15 U to 60 U-   (e) biceps brachii: 50 U to 200 U. Each of the five indicated    muscles has been injected at the same treatment session, so that the    patient receives from 90 U to 360 U of upper limb flexor muscle    BOTOX® by intramuscular injection at each treatment session.-   (7) to treat migraine, pericranial injected (injected symmetrically    into glabellar, frontalis and temporalis muscles) injection of 25 U    of BOTOX® has showed significant benefit as a prophylactic treatment    of migraine compared to vehicle as measured by decreased measures of    migraine frequency, maximal severity, associated vomiting and acute    medication use over the three month period following the 25 U    injection.

It is known that botulinum toxin type A can have an efficacy for up to12 months (European J. Neurology 6 (Supp 4): S11-S1150:1999), and insome circumstances for as long as 27 months, when used to treat glands,such as in the treatment of hyperhydrosis. See e.g. Bushara K.,Botulinum toxin and rhinorrhea, Otolaryngol Head Neck Surg1996;114(3):507, and The Laryngoscope 109:1344-1346:1999. However, theusual duration of an intramuscular injection of Botox® is typicallyabout 3 to 4 months.

The success of botulinum toxin type A to treat a variety of clinicalconditions has led to interest in other botulinum toxin serotypes. Twocommercially available botulinum type A preparations for use in humansare BOTOX® available from Allergan, Inc., of Irvine, Calif., andDysport® available from Beaufour Ipsen, Porton Down, England. ABotulinum toxin type B preparation (MyoBloc®) is available from ElanPharmaceuticals of San Francisco, Calif.

In addition to having pharmacologic actions at the peripheral location,botulinum toxins may also have inhibitory effects in the central nervoussystem. Work by Weigand et al, Nauny-Schmiedeberg's Arch. Pharmacol.1976; 292,161-165, and Habermann, Nauny-Schmiedeberg's Arch. Pharmacol.1974; 281, 47-56 showed that botulinum toxin is able to ascend to thespinal area by retrograde transport. As such, a botulinum toxin injectedat a peripheral location, for example intramuscularly, may be retrogradetransported to the spinal cord.

A botulinum toxin has also been proposed for or has been used to treatskin bone and tendon wounds (U.S. Pat. No. 6,447,787); intrathecal pain(see e.g. U.S. Pat. No. 6,113,915); various autonomic nerve disorders,including sweat gland disorders (see e.g. U.S. Pat. No. 5,766,605 andGoldman (2000), Aesthetic Plastic Surgery July-August 24(4):280-282);tension headache (U.S. Pat. No. 6,458,365); migraine headache pain (U.S.Pat. No. 5,714,468); post-operative pain and visceral pain (U.S. Pat.No. 6,464,986); hair growth and hair retention (U.S. Pat. No.6,299,893); psoriasis and dermatitis (U.S. Pat. No. 5,670,484); injuredmuscles (U.S. Pat. No. 6,423,319); various cancers (see e.g. U.S. Pat.Nos. 6,139,845 and 6,063,768), smooth muscle disorders (U.S. Pat. No.5,437,291); nerve entrapment syndromes (U.S. patent application 20030224019); acne (WO 03/011333); neurogenic inflammation (U.S. Pat. No.6,063,768); otic disorders (see e.g. U.S. Pat. No. 6,265,379);pancreatic disorders (see e.g. U.S. Pat. Nos. 6,143,306 and 6,261,572);prostate disorders, including prostatic hyperplasia, prostate cancer andurinary incontinence (see e.g. U.S. Pat. Nos. 6,365,164 and 6,667,041and Doggweiler R., et al Botulinum toxin type A causes diffuse andhighly selective atrophy of rat prostate, Neurourol Urodyn1998;17(4):363); fibromyalgia (U.S. Pat. No. 6,623,742), and piriformismuscle syndrome (see e.g. Childers et al. (2002), American Journal ofPhysical Medicine & Rehabilitation, 81:751-759).

U.S. Pat. No. 5,989,545 discloses that a modified clostridial neurotoxinor fragment thereof, preferably a botulinum toxin, chemically conjugatedor recombinantly fused to a particular targeting moiety can be used totreat pain by administration of the agent to the spinal cord.Additionally it has been disclosed that targeted botulinum toxins (i.e.with a non-native binding moiety) can be used to treat variousconditions (see e.g. WO 96/33273; WO 99/17806; WO 98/07864; WO 00/57897;WO 01/21213; WO 00/10598.

A botulinum toxin has been injected into the pectoral muscle to controlpectoral spasm. See e.g. Senior M., Botox and the management of pectoralspasm after subpectoral implant insertion, Plastic and Recon Surg, July2000, 224-225. Controlled release toxin implants are known (see e.g.U.S. Pat. Nos. 6,306,423 and 6,312,708) as is transdermal botulinumtoxin administration (U.S. patent application Ser. No. 10/194805).

Both liquid stable formulations and pure botulinum toxin formulationshave been disclosed (see e.g. WO 00/15245 and WO 74703) as well astopical application of a botulinum toxin (see e.g. DE 198 52 981).

It is known that a botulinum toxin can be used to: weaken the chewing orbiting muscle of the mouth so that self inflicted wounds and resultingulcers can heal (Payne M., et al, Botulinum toxin as a novel treatmentfor self mutilation in Lesch-Nyhan syndrome, Ann Neurol 2002September;52(3 Supp 1):S157); permit healing of benign cystic lesions ortumors (Blugerman G., et al., Multiple eccrine hidrocystomas: A newtherapeutic option with botulinum toxin, Dermatol Surg 2003May;29(5):557-9); treat anal fissure (Jost W., Ten years' experiencewith botulinum toxin in anal fissure, Int J Colorectal Dis 2002September;17(5):298-302, and; treat certain types of atopic dermatitis(Heckmann M., et al., Botulinum toxin type A injection in the treatmentof lichen simplex: An open pilot study, J Am Acad Dermatol 2002April;46(4):617-9).

Additionally, a botulinum toxin may have an effect to reduce inducedinflammatory pain in a rat formalin model. Aoki K., et al, Mechanisms ofthe antinociceptive effect of subcutaneous Botox: Inhibition ofperipheral and central nociceptive processing, Cephalalgia 2003September;23(7):649. Furthermore, it has been reported that botulinumtoxin nerve blockage can cause a reduction of epidermal thickness. Li Y,et al., Sensory and motor denervation influences epidermal thickness inrat foot glabrous skin, Exp Neurol 1997;147:452-462 (see page 459).Finally, it is known to administer a botulinum toxin to the foot totreat excessive foot sweating (Katsambas A., et al., Cutaneous diseasesof the foot: Unapproved treatments, Clin Dermatol 2002November-December;20(6):689-699; Sevim, S., et al., Botulinum toxin-Atherapy for palmar and plantar hyperhidrosis, Acta Neurol Belg 2002December;102(4):167-70), spastic toes (Suputtitada, A., Local botulinumtoxin type A injections in the treatment of spastic toes, Am J Phys MedRehabil 2002 October;81 (10):770-5), idiopathic toe walking (Tacks, L.,et al., Idiopathic toe walking: Treatment with botulinum toxin Ainjection, Dev Med Child Neurol 2002;44(Suppl 91):6), and foot dystonia(Rogers J., et al., Injections of botulinum toxin A in foot dystonia,Neurology 1993 April;43(4 Suppl 2)).

Tetanus toxin, as wells as derivatives (i.e. with a non-native targetingmoiety), fragments, hybrids and chimeras thereof can also havetherapeutic utility. The tetanus toxin bears many similarities to thebotulinum toxins. Thus, both the tetanus toxin and the botulinum toxinsare polypeptides made by closely related species of Clostridium(Clostridium tetani and Clostridium botulinum, respectively).Additionally, both the tetanus toxin and the botulinum toxins aredichain proteins composed of a light chain (molecular weight about 50kD) covalently bound by a single disulfide bond to a heavy chain(molecular weight about 100 kD). Hence, the molecular weight of tetanustoxin and of each of the seven botulinum toxins (non-complexed) is about150 kD. Furthermore, for both the tetanus toxin and the botulinumtoxins, the light chain bears the domain which exhibits intracellularbiological (protease) activity, while the heavy chain comprises thereceptor binding (immunogenic) and cell membrane translocationaldomains.

Further, both the tetanus toxin and the botulinum toxins exhibit a high,specific affinity for gangliocide receptors on the surface ofpresynaptic cholinergic neurons. Receptor mediated endocytosis oftetanus toxin by peripheral cholinergic neurons results in retrogradeaxonal transport, blocking of the release of inhibitoryneurotransmitters from central synapses and a spastic paralysis.Contrarily, receptor mediated endocytosis of botulinum toxin byperipheral cholinergic neurons results in little if any retrogradetransport, inhibition of acetylcholine exocytosis from the intoxicatedperipheral motor neurons and a flaccid paralysis.

Finally, the tetanus toxin and the botulinum toxins resemble each otherin both biosynthesis and molecular architecture. Thus, there is anoverall 34% identity between the protein sequences of tetanus toxin andbotulinum toxin type A, and a sequence identity as high as 62% for somefunctional domains. Binz T. et al., The Complete Sequence of BotulinumNeurotoxin Type A and Comparison with Other Clostridial Neurotoxins, JBiological Chemistry 265(16);9153-9158:1990.

Acetylcholine

Typically only a single type of small molecule neurotransmitter isreleased by each type of neuron in the mammalian nervous system,although there is evidence which suggests that several neuromodulatorscan be released by the same neuron. The neurotransmitter acetylcholineis secreted by neurons in many areas of the brain, but specifically bythe large pyramidal cells of the motor cortex, by several differentneurons in the basal ganglia, by the motor neurons that innervate theskeletal muscles, by the preganglionic neurons of the autonomic nervoussystem (both sympathetic and parasympathetic), by the bag 1 fibers ofthe muscle spindle fiber, by the postganglionic neurons of theparasympathetic nervous system, and by some of the postganglionicneurons of the sympathetic nervous system. Essentially, only thepostganglionic sympathetic nerve fibers to the sweat glands, thepiloerector muscles and a few blood vessels are cholinergic as most ofthe postganglionic neurons of the sympathetic nervous system secret theneurotransmitter norepinephine. In most instances acetylcholine has anexcitatory effect. However, acetylcholine is known to have inhibitoryeffects at some of the peripheral parasympathetic nerve endings, such asinhibition of heart rate by the vagal nerve.

The efferent signals of the autonomic nervous system are transmitted tothe body through either the sympathetic nervous system or theparasympathetic nervous system. The preganglionic neurons of thesympathetic nervous system extend from preganglionic sympathetic neuroncell bodies located in the intermediolateral horn of the spinal cord.The preganglionic sympathetic nerve fibers, extending from the cellbody, synapse with postganglionic neurons located in either aparavertebral sympathetic ganglion or in a prevertebral ganglion. Since,the preganglionic neurons of both the sympathetic and parasympatheticnervous system are cholinergic, application of acetylcholine to theganglia will excite both sympathetic and parasympathetic postganglionicneurons.

Acetylcholine activates two types of receptors, muscarinic and nicotinicreceptors. The muscarinic receptors are found in all effector cellsstimulated by the postganglionic, neurons of the parasympathetic nervoussystem as well as in those stimulated by the postganglionic cholinergicneurons of the sympathetic nervous system. The nicotinic receptors arefound in the adrenal medulla, as well as within the autonomic ganglia,that is on the cell surface of the postganglionic neuron at the synapsebetween the preganglionic and postganglionic neurons of both thesympathetic and parasympathetic systems. Nicotinic receptors are alsofound in many nonautonomic nerve endings, for example in the membranesof skeletal muscle fibers at the neuromuscular junction.

Acetylcholine is released from cholinergic neurons when small, clear,intracellular vesicles fuse with the presynaptic neuronal cell membrane.A wide variety of non-neuronal secretory cells, such as, adrenal medulla(as well as the PC12 cell line) and pancreatic islet cells releasecatecholamines and parathyroid hormone, respectively, from largedense-core vesicles. The PC12 cell line is a clone of ratpheochromocytoma cells extensively used as a tissue culture model forstudies of sympathoadrenal development. Botulinum toxin inhibits therelease of both types of compounds from both types of cells in vitro,permeabilized (as by electroporation) or by direct injection of thetoxin into the denervated cell. Botulinum toxin is also known to blockrelease of the neurotransmitter glutamate from cortical synaptosomescell cultures.

A neuromuscular junction is formed in skeletal muscle by the proximityof axons to muscle cells. A signal transmitted through the nervoussystem results in an action potential at the terminal axon, withactivation of ion channels and resulting release of the neurotransmitteracetylcholine from intraneuronal synaptic vesicles, for example at themotor endplate of the neuromuscular junction. The acetylcholine crossesthe extracellular space to bind with acetylcholine receptor proteins onthe surface of the muscle end plate. Once sufficient binding hasoccurred, an action potential of the muscle cell causes specificmembrane ion channel changes, resulting in muscle cell contraction. Theacetylcholine is then released from the muscle cells and metabolized bycholinesterases in the extracellular space. The metabolites are recycledback into the terminal axon for reprocessing into further acetylcholine.

What is needed therefore is a non-surgical method for effectivelytreating a buttock deformity.

SUMMARY

The present invention meets this need and provides methods foreffectively treating a buttock deformity by local administration of aClostridial neurotoxin, such as a botulinum toxin.

The following definitions apply herein:

“About” means approximately or nearly and in the context of a numericalvalue or range set forth herein means±10% of the numerical value orrange recited or claimed.

“Asymmetric ptosis of the buttock” means a buttock which sag or droopssuch that it has a decreased symmetry with regard to the other buttock.

“Botulinum toxin” means a botulinum neurotoxin (i.e. the botulinumneurotoxins types A, B, C, D, E, F and G) as either pure toxin (i.e.about 150 kDa weight molecule) or as a complex (i.e. about 300 to about900 kDa weight complex comprising the neurotoxin molecule and one ormore associated non-toxic molecules), and excludes botulinum toxinswhich are not neurotoxins such as the cytotoxic botulinum toxins C2 andC3, but includes recombinantly made, hybrid, modified, and chimericbotulinum neuro toxins.

“Buttock” means the gluteus maximus, gluteus medius, and/or gluteusminimus muscles, and the structures and tissues directly attendant tothese muscles such as associated joints, tendons, ligaments, adiposetissues and overlying dermis.

“Buttock modification exercise” means an exercise carried out to stretchand/or strengthen a buttock muscle or attendant structure.

“Contour deformity” means a buttock with an undesirable shape orappearance.

“Deficient buttock” means a buttock that is at least 10% smaller thanthe average length, width and/or prominence of a buttock of persons ofthe same or similar size and weight as the patient.

“Deformity” means a cosmetic, physical or functional irregularity,defect, abnormality, imperfection, malformation or distortion. A“buttock deformity” excludes any buttock glandular deformity or defect,such as that of a secreting (including an excessively secreting) buttocksweat gland, because treatment of a buttock glandular defect is excludedfrom the scope of the present invention as treatment of a buttock glandcan be difficult, painful, time consuming and therapeuticallyunsatisfactory to the patient and/or to the treating physician due tothe sensitive nature of buttock tissues and the dispersed distributionof buttock glands, including buttock sweat glands. Moreover, treatingbuttock region sweat glands (to reduce the sweating) can havedeleterious side effects. For example, in buttock deformity treatmentswhere stretching and strengthening exercises are employed, sweatingwould be a desirable consequence to prevent overheating caused by thestretching and strengthening exercises. Also, treatment of a buttockdeformity according to the present invention excludes administration ofa botulinum toxin to a piriformis muscle because the piriformis muscleis a deep muscle that is not involved in buttock shaping or reshaping orin the ambulatory process. In addition, treatment to a piriformis musclecan cause unnecessary pain and unwanted functional side effects such asan inability to rotate or abduct a thigh. Furthermore, treatment of abuttock deformity excludes treatment of pain associated with the buttockbecause pain is a sensory perception and not a motor function involvedin movement or providing structural support. Moreover, in treatment ofbuttock deformity where stretching and strengthening exercises areinvolved, pain is a necessary and a desired sensory perception to beretained so as to prevent or to signal overexertion and over-stretching.

“Depression in the buttock” means that the shape of the overall buttockis interrupted by a concavity in a portion of the buttock.

“Flat buttock” means one where there is a decreased overall curvature ofthe outline of the buttock (from a profile view) compared to the averagebuttock of other persons of the same or similar size and weight.

“Foot supporting device” means any device, such an orthotic or lift,used to improve gait or posture or to reduce pain caused by deformitiesin the back, hip, and/or lower extremities.

“Irregularly shaped buttock” means a buttock that deviates from theaverage shape of a buttock of persons of the same or similar size andweight as the patient

“Lack of a buttock” means absent of a buttock or lack of substantiallyall of a buttock.

“Large buttock” means a buttock which is at least 10% larger (in width,length or prominence, i.e. depth) as compared to the size of the averagebuttock of persons the same or similar size and weight as the patient.

“Local administration” or “locally administering” means administration(i.e. by injection, implantation or topical application) by anon-systemic route (such as by a subcutaneous, intramuscular, subdermal,intradermal or transdermal route, whereby insignificant amounts of thepharmaceutical agent appear systemically) of a pharmaceutical agent toor to the vicinity of a target dermal or subdermal location (such as toa muscle) of a patient.

“Prominent buttock” means a buttock that has a shape that noticeablyprotrudes outward compared to the average buttock of other persons ofthe same or similar size and weight of the patient.

“Square buttock” means that buttock when viewed directly from the rearhas a decreased overall curvature of the outline of the buttock ascompared to the average buttock of other persons of the same or similarsize and weight as the patient.

“Therapeutically effective amount” means the level, amount orconcentration of an agent (i.e. an active pharmaceutical ingredient,such as a botulinum toxin) needed to treat a disease, disorder orcondition without causing significant negative or adverse side effectsto the treated tissue.

“Treat”, “treating”, or “treatment” means an alleviation or a reduction(which includes some reduction, a significant reduction a near totalreduction, and a total reduction), resolution or prevention (temporarilyor permanently) of an disease, disorder or condition, such as a buttockdeformity, so as to achieve a desired therapeutic or cosmetic result,such as by healing of injured or damaged tissue, or by altering,changing, enhancing, improving, ameliorating and/or beautifying anexisting or perceived disease, disorder or condition. A treatmenteffect, such as an alleviating effect from administration of a botulinumneurotoxin may not appear clinically for between 1 to 7 days afteradministration of the botulinum neurotoxin to a patient.

“Trauma” means an injury, disease, malady or complication includingtrauma due to a medical procedure, such as surgery.

“Uneven buttock crease and fold” means the crease and fold of one sideof the buttock is not aligned with the crease and fold of the other sideof the same buttock.

A method within the scope of the present invention for treating abuttock deformity can have the step of local administration of aClostridial neurotoxin (such as a botulinum toxin) into or to a buttockof a patient, thereby treating the buttock deformity.

The buttock musculature have functions in stability and gait. Botulinumtoxin is known to have a relaxation effect on muscle and according tothe present invention can be used to treat a buttock deformity, throughits affect on buttock musculature. Inhibition of acetylcholine releaseby buttock motor neurons can result in relaxation of the innervatedmuscle and thereby achieving a symmetrical shape buttock upon injectingthe affected muscles. Additionally, according to my invention buttockfolds or wrinkles can also be treated with a botulinum toxin. Injectionof a therapeutic amount of a selected serotype of a botulinum toxin canenhance gait and symmetry. In addition to these subcutaneous andintramuscular injections, buttock deformities that cause dysfunctionaround the sacroiliac joint can be treated by an intra-articularinjection of a bbtulinum toxin into the sacroiliac joint to therebyrelieve pain and improve gait.

The botulinum neurotoxin can be locally administered in an amount ofbetween about 10⁻³ units/kg of patient weight and about 35 units/kg ofpatient weight. Preferably, the neurotoxin is locally administered in anamount of between about 10⁻² U/kg and about 25 U/kg of patient weight.More preferably, the neurotoxin is administered in an amount of betweenabout 10⁻¹ U/kg and about 15 U/kg. In a particularly preferred methodwithin the scope of the present invention, the neurotoxin is locallyadministered in an amount of between about 1 U/kg and about 10 U/kg. Ina clinical setting it can be advantageous to inject from 1 U to 3000 Uof a neurotoxin, such as botulinum toxin type A or B, to a buttock bytopical application or by subdermal administration, to effectively treatthe buttock deformity.

An embodiment of the present invention is a method for treating abuttock deformity, the method comprising the step of administering abotulinum toxin to a buttock of a patient, thereby treating the buttockdeformity. Preferably, the botulinum toxin is selected from the groupconsisting of botulinum toxin types A, B, C, D, E, F and G and morepreferably, the botulinum toxin is a botulinum toxin type A. Thebotulinum toxin is administered intramuscularly, into a gluteal muscle,in an amount of between about 1 unit and about 3,000 units, wherein thegluteal muscle is selected from the group consisting of a gluteusmaximus, gluteus medius and gluteus minimus.

The buttock deformity can be a contour deformity, wherein the contourdeformity is selected from a group consisting of large buttock,prominent buttock, deficient buttock, flat buttock, lack of a buttock,uneven buttock crease and fold, depressions in the buttock, squarebuttock shapes, asymmetric ptosis of the buttock and irregularly shapedbuttock.

A detailed embodiment of the present invention is a method of treating abuttock deformity, the method comprising the step of locallyadministering a therapeutically effective amount of a botulinum toxin toa buttock deformity of the patient, thereby treating a buttock byremoving or reducing the occurrence of the buttock deformity, whereinthe treatment of the buttock deformity results in improved gait orenhanced symmetry.

Another embodiment of the present invention is a method for treating abuttock deformity, the method comprising the steps of (a) a buttockmodification exercise in conjunction with administering a botulinumtoxin to a buttock and (b) administering the botulinum toxin to abuttock, thereby treating the buttock deformity. Preferably, thebotulinum toxin is selected from the group consisting of botulinum toxintypes A, B, C, D, E, F and G and more preferably, the botulinum toxin isa botulinum toxin type A and is administered in an amount of betweenabout 1 unit and about 3,000 units.

A detailed embodiment of the present invention is a method for treatinga buttock deformity, the method comprising the steps of (a) a buttockmodification exercise in conjunction with administering a botulinumtoxin and (b) administering between 1 and about 3,000 units of botulinumtoxin type A to a buttock, thereby treating the buttock deformity.

A third embodiment of the present invention is a method for treating abuttock deformity, the method comprising the steps of (a) using a footsupporting device in conjunction with administration of a botulinumtoxin and (b) administering a botulinum toxin into a buttock, therebytreating the buttock deformity. Preferably, the botulinum toxin isselected from the group consisting of botulinum toxin types A, B, C, D,E, F and G and more preferably, the botulinum toxin is a botulinum toxintype A and is administered in an amount of between about 1 unit andabout 3,000 units.

A detailed embodiment of the present invention is a method for treatinga buttock deformity, the method comprising the steps of (a) using a footsupporting device in conjunction with administering a botulinum toxinand (b) administering between 1 and about 3,000 units of botulinum toxintype A to a buttock, thereby treating the buttock deformity.

A fourth embodiment of the present invention is a method for treating anunderdeveloped gluteal muscle, the method comprising the step ofadministering a botulinum toxin underneath a buttock fold, therebytreating the underdeveloped gluteal muscle. Preferably, the botulinumtoxin is selected from the group consisting of botulinum toxin types A,B, C, D, E, F and G and more preferably, the botulinum toxin is abotulinum toxin type A and is administered in an amount of between about1 unit and about 3,000 units.

A detailed embodiment of the present invention is a method for treatingan underdeveloped gluteal muscle, the method comprising the steps ofadministering between 1 and about 3,000 units of botulinum toxin type Aunderneath a buttock fold, thereby treating the underdeveloped glutealmuscle.

A fifth embodiment of the present invention is a method for treating anarthrogenic inhibition of a gluteus maximus, the method comprising thesteps of (a) administering a botulinum toxin into a buttock and (b)administering a botulinum toxin into a joint, thereby treating thearthrogenic inhibition. Preferably, the botulinum toxin is selected fromthe group consisting of botulinum toxin types A, B, C, D, E, F and G andmore preferably, the botulinum toxin is a botulinum toxin type A and isadministered in an amount of between about 1 unit and about 3,000 units.The buttock is a gluteus maximus ipsilateral to the arthrogenicinhibition and/or a gluteus medius contralateral to the arthrogenicinhibition. The joint can be a sacroiliac joint.

A detailed embodiment of the present invention is a method for treatingan arthrogenic inhibition of a gluteus maximus, the method comprisingthe steps of administering between 1 and about 3,000 units of botulinumtoxin type A to (a) a gluteus maximus ipsilateral to the arthrogenicinhibition, (b) a gluteus medius contralateral to the arthrogenicinhibition, and (c) to a sacroiliac joint, thereby treating thearthrogenic inhibition of the gluteus maximus.

A suitable neurotoxin for use in the practice of the present inventioncan be made by a Clostridial bacterium, such as Clostridium botulinum,Clostridium butyricum or Clostridium beratti. The neurotoxin use can bea modified neurotoxin, that is, a neurotoxin has had at least one of itsamino acids deleted, modified or replaced, as compared to a nativeneurotoxin. Additionally, the neurotoxin can be recombinantly madeproduced neurotoxin or a derivative or fragment of a recombinant madeneurotoxin. The neurotoxin can be a botulinum toxin, such as one of thebotulinum toxin serotypes A, B, C, D, E, F or G. A preferred botulinumtoxin to use in the practice of the present invention is botulinum toxintype A.

A method according to my invention can be carried out by administrationof a Clostridial toxin to a patient with, or who is predisposed todeveloping, a buttock deformity. The Clostridial toxin used ispreferably a botulinum toxin (as either a complex or as a pure [i.e.about 150 kDa molecule], such as a botulinum neurotoxin A, B, Cl, D, E,F or G. Administration of the Clostridial toxin can be by a transdermalroute (i.e. by application of a Clostridial toxin in a cream, patch orlotion vehicle), subdermal route (i.e. subcutaneous or intramuscular) orintradermal route of administration.

The Clostridial neurotoxin is administered in a therapeuticallyeffective amount to alleviate a symptom of a buttock deformity. Asuitable Clostridial neurotoxin may be a neurotoxin made by a bacterium,for example, the neurotoxin may be made from a Clostridium botulinum,Clostridium butyricum, or Clostridium beratti. In certain embodiments ofthe invention, the buttock deformity can be treated by injecting abotulinum toxin intramuscularly. The botulinum toxin can be a botulinumtoxin type A, type B, type C1, type D, type E, type F, or type G. Thebuttock deformity alleviating effects of the botulinum toxin may persistfor between about 2 weeks (i.e. upon administration of a short actingbotulinum toxin, such as a botulinum toxin type E or F) and 5 years(i.e. upon implantation of a controlled release botulinum toxinimplant). The botulinum neurotoxin can be a recombinantly made botulinumneurotoxins, such as botulinum toxins produced by an E. coli bacterium.In addition or alternatively, the botulinum neurotoxin can be a modifiedneurotoxin, that is a botulinum neurotoxin which has at least one of itsamino acids deleted, modified or replaced, as compared to a native orthe modified botulinum neurotoxin can be a recombinant producedbotulinum neurotoxin or a derivative or fragment thereof.

DESCRIPTION

The present invention is based upon the discovery that a buttockdeformity can be treated by local administration of a therapeuticallyeffective amount of a Clostridial neurotoxin, such as a botulinumneurotoxin. The botulinum neurotoxin (such as a botulinum neurotoxinserotype A, B, C, D, E, F or G) can be administered by topicalapplication, subdermal injection or intramuscular injection into abuttock of a patient.

My invention includes methods for treating at least the following typesof buttock deformities; asymmetric buttock, large buttock, prominentbuttock, irregular buttock, deficient buttock, flat buttock, unevenbuttock, depressions in the buttock, and square buttock. A botulinumtoxin can be applied in an effective therapeutic amount by applyingabout one unit of a botulinum toxin type A/cm2 of the affected area.Methods to apply the botulinum toxin include but are not limited tosubcutaneous, intradermal, intramuscular, topical, and via slow orextended release implants.

Thus, my invention includes use of a botulinum toxin to treat a buttockdeformity by causing it to become flaccid and/or to relieve the pain andinflammation that can accompany a buttock deformity.

The amount of the Clostridial toxin administered according to a methodwithin the scope of the disclosed invention can vary according to theparticular characteristics of the buttock deformity being treated,including its severity and other various patient variables includingsize, weight, age, and responsiveness to therapy. To guide thepractitioner, typically, no less than about 5 units and no more thanabout 500 units of a botulinum toxin type A (such as BOTOX®)) isadministered per injection site (i.e. to each buttock deformity locationinjected), per patent treatment session. For a botulinum toxin type Asuch as DYSPORT®, preferably no less than about 10 units and no moreabout 2000 units of the botulinum toxin type A are administered peradministration or injection site, per patent treatment session. For abotulinum toxin type B such as MYOBLOC®, preferably no less than about200 units and no more than about 25000 units of the botulinum toxin typeB are administered per administer or injection site, per patienttreatment session. Less than about 5, 10 or 200 units (of BOTOX®,DYSPORTO® and MYOBLOC® respectively) can fail to achieve a desiredtherapeutic effect, while more than about 500, 2000 or 25000 units (ofBOTOX®), DYSPORT® and MYOBLOC® respectively) can result in clinicallyobservable and undesired muscle hypotonicity, weakness and/or paralysis.

More preferably: for BOTOX® no less than about 10 units and no moreabout 400 units of a botulinum toxin type A; for DYSPORT® no less thanabout 30 units and no more than about 1600 units, and; for MYOBLOC®), noless than about 250 units and no more than about 20000 units are,respectively, administered per injection site, per patient treatmentsession.

Most preferably: for BOTOX® no less than about 20 units and no moreabout 300 units of a botulinum toxin type A; for DYSPORT® no less thanabout 60 units and no more than about 1200 units, and; for MYOBLOC®, noless than about 1000 units and no more than about 15000 units are,respectively, administered per injection site, per patient treatmentsession. It is important to note that there can be multiple injectionsites (i.e. a pattern of injections) for each patient treatment session.

Although examples of routes of administration and dosages are provided,the appropriate route of administration and dosage are generallydetermined on a case by case basis by the attending physician. Suchdeterminations are routine to one of ordinary skill in the art (see forexample, Harrison's Principles of Intemal Medicine (1998), edited byAnthony Fauci et al., 14th edition, published by McGraw Hill). Forexample, the route and dosage for administration of a Clostridialneurotoxin according to the present disclosed invention can be selectedbased upon criteria such as the solubility characteristics of theneurotoxin chosen as well as the intensity and scope of a buttockdeformity.

The present invention is based on the discovery that localadministration of a Clostridial toxin can provide significant and longlasting relief from a buttock deformity. A Clostridial toxin used inaccordance with the invention disclosed herein can inhibit transmissionof chemical or electrical signals between select neuronal groups thatare involved in generation of a buttock deformity. The Clostridialtoxins preferably are not cytotoxic to the cells that are exposed to theClostridial toxin. The Clostridial toxin can inhibit neurotransmissionby reducing or preventing exocytosis of neurotransmitter from theneurons exposed to the Clostridial toxin. Alternatively, the appliedClostridial toxin can reduce neurotransmission by inhibiting thegeneration of action potentials of the neurons exposed to the toxin. Thebuttock deformity alleviation effect provided by the Clostridial toxincan persist for a relatively long period of time, for example, for morethan two months (or for 2-4 weeks upon use of a botulinum toxin type Eor F), and potentially for several years.

Examples of Clostridial toxins within the scope of the present inventioninclude neurotoxins made by Clostridium botulinum, Clostridium butyricumand Clostridium beratti species. In addition, the botulinum toxins usedin the methods of the invention can be a botulinum neurotoxin selectedfrom a group of botulinum toxin types A, B, C1, D, E, F, and G. In oneembodiment of the invention, the botulinum neurotoxin administered tothe patient is botulinum toxin type A. Botulinum toxin type A isdesirable due to its high potency in humans, ready availability, andknown use for the treatment of skeletal and smooth muscle disorders whenlocally administered by intramuscular injection. The present inventionalso includes the use of (a) Clostridial neurotoxins obtained orprocessed by bacterial culturing, toxin extraction, concentration,preservation, freeze drying, and/or reconstitution; and/or (b) modifiedor recombinant neurotoxins, that is neurotoxins that have had one ormore amino acids or amino acid sequences deliberately deleted, modifiedor replaced by known chemical/biochemical amino acid modificationprocedures or by use of known host cell/recombinant vector recombinanttechnologies, as well as derivatives or fragments of neurotoxins somade. These neurotoxin variants retain the ability to inhibitneurotransmission between or among neurons, and some of these variantsmay provide increased durations of inhibitory effects as compared tonative neurotoxins, or may provide enhanced binding specificity to theneurons exposed to the neurotoxins. These neurotoxin variants may beselected by screening the variants using conventional assays to identifyneurotoxins that have the desired physiological effects of inhibitingneurotransmission.

Botulinum toxins for use according to the present invention can bestored in lyophilized, vacuum dried form in containers under vacuumpressure or as stable liquids. Prior to lyophilization the botulinumtoxin can be combined with pharmaceutically acceptable excipients,stabilizers and/or carriers, such as albumin. The lyophilized materialcan be reconstituted with saline or water to create a solution orcomposition containing the botulinum toxin to be administered to thepatient.

Although the composition may only contain a single type of neurotoxin,such as botulinum toxin type A, as the active ingredient to suppressneurotransmission, other therapeutic compositions may include two ormore types of neurotoxins, which may provide enhanced therapeutictreatment of a buttock deformity. For example, a compositionadministered to a patient may include botulinum toxin type A andbotulinum toxin type B. Administering a single composition containingtwo different neurotoxins can permit the effective concentration of eachof the neurotoxins to be lower than if a single neurotoxin isadministered to the patient while still achieving the desiredtherapeutic effects. The composition administered to the patient mayalso contain other pharmaceutically active ingredients, such as, proteinreceptor or ion channel modulators, in combination with the neurotoxinor neurotoxins. These modulators may contribute to the reduction inneurotransmission between the various neurons. For example, acomposition may contain gamma aminobutyric acid (GABA) type A receptormodulators that enhance the inhibitory effects mediated by the GABAAreceptor. The GABAA receptor inhibits neuronal activity by effectivelyshunting current flow across the cell membrane. GABAA receptormodulators may enhance the inhibitory effects of the GABM receptor andreduce electrical or chemical signal transmission from the neurons.Examples of GABAA receptor modulators include benzodiazepines, such asdiazepam, oxaxepam, lorazepam, prazepam, alprazolam, halazeapam,chordiazepoxide, and chlorazepate. Compositions may also containglutamate receptor modulators that decrease the excitatory effectsmediated by glutamate receptors. Examples of glutamate receptormodulators include agents that inhibit current flux through AMPA, NMDA,and/or kainate types of glutamate receptors. The compositions may alsoinclude agents that modulate dopamine receptors, such as antipsychotics,norepinephrine receptors, and/or serotonin receptors. The compositionsmay also include agents that affect ion flux through voltage gatedcalcium channels, potassium channels, and/or sodium channels. Thus, thecompositions used to treat a buttock deformity can include one or moreneurotoxins, such as botulinum toxins, in addition to ion channelreceptor modulators that may reduce neurotransmission.

The neurotoxin may be administered by any suitable method as determinedby the attending physician. The methods of administration permit theneurotoxin to be administered locally to a selected target tissue.Methods of administration include injection of a solution or compositioncontaining the neurotoxin, as described above, and include implantationof a controlled release system that controllably releases the neurotoxinto the target tissue. Such controlled release systems reduce the needfor repeat injections. Diffusion of biological activity of a botulinumtoxin within a tissue appears to be a function of dose and can begraduated. Jankovic J., et al Therapy With Botulinum Toxin, MarcelDekker, Inc., (1994), page 150. Thus, diffusion of botulinum toxin canbe controlled to reduce potentially undesirable side effects that mayaffect the patient's cognitive abilities. For example, the neurotoxincan be administered so that the neurotoxin primarily affects neuralsystems believed to be involved in the generation of a buttockdeformity. A polyanhydride polymer, Gliadel® (Stolle R & D, Inc.,Cincinnati, Ohio) a copolymer of poly-carboxyphenoxypropane and sebacicacid in a ratio of 20:80 has been used to make implants, and has beenintracranially implanted to treat malignant gliomas. Polymer and BCNUcan be co-dissolved in methylene chloride and spray-dried intomicrospheres. The microspheres can then be pressed into discs 1.4 cm indiameter and 1.0 mm thick by compression molding, packaged in aluminumfoil pouches under nitrogen atmosphere and sterilized by 2.2 megaRads ofgamma irradiation. The polymer permits release of carmustine over a 2-3week period, although it can take more than a year for the polymer to belargely degraded. Brem, H., et al, Placebo-Controlled Trial of Safetyand Efficacy of lntraoperative Controlled Delivery by BiodegradablePolymers of Chemotherapy for Recurrent Gliomas, Lancet 345;1008-1012:1995.

Implants useful in practicing the methods disclosed herein may beprepared by mixing a desired amount of a stabilized neurotoxin (such asnon-reconstituted BOTOX®) into a solution of a suitable polymerdissolved in methylene chloride. The solution may be prepared at roomtemperature. The solution can then be transferred to a Petri dish andthe methylene chloride evaporated in a vacuum desiccator. Depending uponthe implant size desired and hence the amount of incorporatedneurotoxin, a suitable amount of the dried neurotoxin incorporatingimplant is compressed at about 8000 p.s.i. for 5 seconds or at 3000p.s.i. for 17 seconds in a mold to form implant discs encapsulating theneurotoxin. See e.g. Fung L. K. et al., Pharmacokinetics of InterstitialDelivery of Carmustine 4-Hydroperoxycyclophosphamide and Paclitaxel Froma Biodegradable Polymer Implant in the Monkey Brain, Cancer Research 58;672-684:1998.

Local administration of a Clostridial toxin, such as a botulinum toxin,can provide a high, local therapeutic level of the toxin. A controlledrelease polymer capable of long term, local delivery of a Clostridialtoxin to a target buttock deformity location permits effective dosing ofthe target tissue. A suitable implant, as set forth in U.S. Pat. No.6,306,423 entitled “Neurotoxin Implant”, allows the direct introductionof a chemotherapeutic agent to a target tissue via a controlled releasepolymer. The implant polymers used are preferably hydrophobic so as toprotect the polymer incorporated neurotoxin from water induceddecomposition until the toxin is released into the target tissueenvironment.

Local administration of a botulinum toxin, according to the presentinvention, by injection or implant to a target tissue provides asuperior alternative to systemic administration of pharmaceuticals topatients to alleviate a buttock deformity.

The amount of a Clostridial toxin selected for local administration to atarget tissue according to the present disclosed invention can be variedbased upon criteria such as the severity of the buttock deformity beingtreated, solubility characteristics of the neurotoxin toxin chosen aswell as the age, sex, weight and health of the patient. For example, theextent of the area of muscle influenced is believed to be proportionalto the volume of neurotoxin injected, while the quantity of the buttockdeformity suppressant effect is, for most dose ranges, believed to beproportional to the concentration of a Clostridial toxin administered.Methods for determining the appropriate route of administration anddosage are generally determined on a case by case basis by the attendingphysician. Such determinations are routine to one of ordinary skill inthe art (see for example, Harrison's Principles of Internal Medicine(1998), edited by Anthony Fauci et al., 14th edition, published byMcGraw Hill).

Significantly, a method within the scope of the present invention canprovide improved patient function. “Improved patient function” can bedefined as an improvement measured by factors such as a reduced pain,reduced time spent in bed, increased ambulation, healthier attitude,more varied lifestyle and/or healing permitted by normal muscle tone.Improved patient function is synonymous with an improved quality of life(QOL). QOL can be assessed using, for example, the known SF-12 or SF-36health survey scoring procedures. SF-36 assesses a patient's physicaland mental health in the eight domains of physical functioning, rolelimitations due to physical problems, social functioning, bodily pain,general mental health, role limitations due to emotional problems,vitality and general health perceptions. Scores obtained can be comparedto published values available for various general and patientpopulations.

EXAMPLES

The following non-limiting examples provide those of ordinary skill inthe art with specific preferred methods to treat conditions within thescope of the present invention and are not intended to limit the scopeof the invention. In the following examples various modes ofnon-systemic administration of a Clostridial neurotoxin can be carriedout. For example, by topical application (cream or transdermal patch),subcutaneous injection, intramuscular injection or by implantation of acontrolled release implant.

Example 1 Use of Botulinum Toxin to Treat a Buttock Deformity Due to aLimb-Length Discrepancy

A 21 year old female can have been followed in a podiatry clinic sinceage 13 for a functional limb length discrepancy that can be related toabnormal pronation of the foot. Upon examination, it can be determinedthat the patient has excessive pronation in longer limb and supinationin shorter limb. That the right arm, shorter (affected side) than theleft, hangs away from the body, while the left arm (long side) can restagainst the body. The patient can have difference in levels ofmalleolar, knee and hip positions; uneven shoulder height, and hergluteal fold lower on short side and iliac crests can be uneven, withthe appearance of dimpling of the left gluteus maximus. In addition tothe functional issues, the patient can also have significant concernsregarding her misshapen gluteal appearance.

Initial treatment can include muscle strengthening and stretchingexercises. However, no or insufficient changes may be noted in thepronation or pain generated by the abnormal posturing. The patient canhave been referred to a podiatrist who can fit her with an orthotic forsix months, as a functional orthotic device in an attempt to correct thepronatory motion, but the results may have been unsatisfactory. Withoutwanting to undergo an invasive surgical procedure, the patient can agreeto a course of botulinum toxin type A in an effort to correct theasymmetry of the gluteal folds and the apparent limb-length inequality.The gluteus maximus on the right side, the affected limb, and of thegluteus medius, on the contralateral side, can be injectedintramuscularly with 100 U and 75 U respectively of BOTOX®. Alternatelyabout 300-400 units of a botulinum toxin type A such as Dysport® orabout 5000 units of a botulinum toxin type B such as MyoBloc® can beused. Upon follow-up one month later, corrections to the patient'sposture and asymmetry can be noted. Upon further examination, theirregularity of gluteal asymmetry and dimpling can have almost totallyresolved. The patient can report one month later an almost symmetricappearance of her gluteal muscles, and a more active social life.

Example 2 Use of Botulinum Toxin to Treat a Buttock Deformity Due toUnderdeveloped Gluteal Muscles

A 31 year old male weightlifter can request buttock sculpting to augmenthis underdeveloped gluteal muscles to give him a more balanced look toimprove overall body aesthetics which is important to him as the patientcompetes in bodybuilding competitions. Since the patient can have lessactual body fat percentage than normal to undergo liposuction sculpting,the patient can agree to a course of neurosculpting therapy using abotulinum toxin type A (BOTOX®). The clinician can inject subcutaneously75 units just under the buttock folds bilaterally using 100 U per side(or alternately about 300-400 units of a botulinum toxin type A such asDysport® or about 5000 units of a botulinum toxin type B such asMyoBloc®). Upon follow up a symmetric appearance with a prominent fold(relaxation of the gluteal muscles can result in defined rounded withslight downward direction) can be noted. The patient can be very pleasedwith the results, reporting no adverse events and that he was the firstplace contestant in a major bodybuilding competition a one month later.cl Example 3

Use of Botulinum Toxin to Treat a Buttock Deformity Due to Spasms of theIliacus and Arthrogenic Inhibition of the Gluteus Maximus

A 48 year old male can be seen in an orthopedics clinic reportingpainful spasms of the iliacus, and of sacroiliac joint. Uponexamination, there can be revealed an arthrogenic inhibition of thegluteus maximus on the side of the blocked joint and of the gluteusmedius on the contralateral side, causing an asymmetric of his buttocks.Since this is often a result of a typical pattern of changes in muscleactivation a course of a botulinum toxin type A (BOTOX®) can be decidedupon and 75 U can be injected into the affected gluteus maximus, 50 Uinto the gluteus medius, and 100 U injected intra-articularly into thesacroiliac joint space. Alternately about 300-400 units of a botulinumtoxin type A such as DYSPORT® or about 5000 units of a botulinum toxintype B such as MYOBLOC® can be used. Upon follow-up 6 weeks later thepatient can report significant reductions in pain and spasm, and uponexamination symmetrical buttock shape can be noted.

Example 4 Use of Botulinum Toxin to Treat a Buttock Deformity Manifestedas an Uneven Buttock due to a Genetic Birth Defect

A 22 year old female can be affected by a genetic birth defect that cancause an uneven buttock crease and fold, depressions in the left buttockand result in an irregularly shaped buttock. The patient can havevisited her aesthetic surgeon as she wishes to enhance her glutealcontour, resulting in a more aesthetic symmetric appearance. Since thepatient can have recently undergone liposuction for the abdominal area,surgery (placement of implants) is not recommended, and therefore, theclinician can recommend a non-invasive trial of a botulinum toxin type A(BOTOX®) to sculpt the affected buttock region. 75 U can be injectedsubcutaneously into the gluteus maximus and 50 U into the gluteusminimus, both on the left side. An additional 50 U can be injectedfollowing small creases and some finer wrinkles. Alternately about300-400 units of a botulinum toxin type A such as DYSPORT® or about 5000units of a botulinum toxin type B such as MYOBLOC® can be used. Uponfollow up examination 1 month later, the asymmetry of the glutealcontour can be 75-85% symmetric. Both the patient and clinician can bepleased with the minimally invasive procedure. The patient can return 3months following the first treatment for a 2^(nd) treatment where therecan be an almost 100% improvement over her original baseline appearance.

In each of the examples above a botulinum toxin type B, C, D, E, F or Gcan be substituted for the botulinum toxin type A used above. Thespecific amount of a botulinum toxin (such as BOTOX®) administereddepends upon a variety of factors to be weighed and considered withinthe discretion of the attending physician and in each of the examplesinsignificant amounts of botulinum toxin enter appear systemically withno significant side effects.

A method for treating a buttock deformity according to the inventiondisclosed herein has many benefits and advantages, including thefollowing:

1. the symptoms of a buttock deformity can be dramatically reduced oreliminated.

2. the symptoms of a buttock deformity can be reduced or eliminated forat least about two weeks to about six months per injection of neurotoxinand for from about one year to about five years upon use of a controlledrelease neurotoxin implant.

3. the injected or implanted Clostridial neurotoxin shows little or notendency to diffuse or to be transported away from the intramuscular (orintradermal or subdermal) injection or implantation site.

4. few or no significant undesirable side effects occur fromintramuscular (or intradermal or subdermal) injection or implantation ofthe Clostridial neurotoxin.

5. the present methods can result in the desirable side effects ofgreater patient mobility, a more positive attitude and an improvedquality of life.

Although the present invention has been described in detail with regardto certain preferred methods, other embodiments, versions, andmodifications within the scope of the present invention are possible.For example, a wide variety of neurotoxins can be effectively used inthe methods of the present invention. Additionally, the presentinvention includes local administration methods to alleviate a buttockdeformity wherein two or more neurotoxins, such as two or more botulinumtoxins, are administered concurrently or consecutively. For example,botulinum toxin type A can be administered until a loss of clinicalresponse or neutralizing antibodies develop, followed by administrationof botulinum toxin type B. Alternately, a combination of any two or moreof the botulinum serotypes A-G can be locally administered to controlthe onset and duration of the desired therapeutic result. Furthermore,non-neurotoxin compounds can be administered prior to, concurrently withor subsequent to administration of the neurotoxin to proved adjuncteffect such as enhanced or a more rapid onset of denervation before theneurotoxin, such as a botulinum toxin, begins to exert its therapeuticeffect.

A botulinum toxin can be administered by itself or in combination of oneor more of the other botulinum toxin serotypes. The botulinum toxin canbe a recombinantly made or a hybrid botulinum toxin.

My invention also includes within its scope the use of a neurotoxin,such as a botulinum toxin, in the preparation of a medicament for thetreatment of a buttock deformity, by local administration of a botulinumneurotoxin.

All references, articles, patents, applications and publications setforth above are incorporated herein by reference in their entireties.

Accordingly, the spirit and scope of the following claims should not belimited to the descriptions of the preferred embodiments set forthabove.

1. A method for treating a buttock deformity, the method comprising thestep of administering a botulium toxin to a buttock of a patient,thereby treating the buttock deformity.
 2. The method of claim 1,wherein the botulinum toxin is selected from the group consisting ofbotulinum toxin types A, B, C, D, E, F and G.
 3. The method of claim 1,wherein the botulinum toxin is a botulinum toxin type A.
 4. The methodof claim 1, wherein the botulinun toxin is administered in an amount ofbetween about 1 unit and about 3,000 units.
 5. The method of claim 1,wherein the administration is by intramuscular administration of thebotulinum toxin.
 6. The method of claim 5, wherein the botulinum toxinis injected intramuscularly into a gluteal muscle.
 7. The method ofclaim 6, wherein the gluteal muscle is selected from the groupconsisting of a gluteus maximus, gluteus medius and gluteus minimusmuscle.
 8. The method of claim 1, wherein the buttock deformity is acontour deformity.
 9. The method of claim 8, wherein the contourdeformity is selected from a group consisting of large buttock,prominent buttock, deficient buttock, flat buttock, lack of a buttock,uneven buttock crease and fold, depressions in the buttock, squarebuttock shapes, asymmetric ptosis of the buttock and irregularly shapedbuttock.
 10. The method of claim 1, the method comprising the step oflocally administering a therapeutically effective amount of a botulinumtoxin to a buttock of the patient, thereby treating a buttock deformityby removing or reducing the occurrence of the buttock deformity.
 11. Themethod of claim 10, wherein the treatment of the buttock deformityresults in improved gait or enhanced symmetry.
 12. A method for treatinga buttock deformity, the method comprising the steps of (a) a buttockmodification exercise in conjunction with administering a botulinumtoxin to a buttock and (b) administering the botulinum toxin to abuttock, thereby treating the buttock deformity.
 13. The method of claim12, wherein the botulinum toxin is selected from the group consisting ofbotulinum toxin types A, B, C, D, E, F and G.
 14. The method of claim12, wherein the botulinum toxin is a botulinum toxin type A.
 15. Themethod of claim 12, wherein the botulinum toxin is administered in anamount of between about 1 unit and about 3,000 units.
 16. A method fortreating a buttock deformity, the method comprising the steps of (a) abuttock modification exercise in conjunction with administering abotulinum toxin and (b) administering between 1 and about 3,000 units ofbotulinum toxin type A to a buttock, thereby treating the buttockdeformity.
 17. A method for treating a buttock deformity, the methodcomprising the steps of (a) using a foot supporting device inconjunction with administration of a botulinum toxin and (b)administering a botulinum toxin into a buttock, thereby treating thebuttock deformity.
 18. The method of claim 17, wherein the botulinunitoxin is selected from the group consisting of botulinum toxin types A,B, C, D, E, F and G.
 19. The method of claim 17, wherein the botulinumtoxin is a botulinum toxin type A.
 20. The method of claim 17, whereinthe botulinum toxin is administered in an amount of between about 1 unitand about 3,000 units.
 21. A method for treating a buttock deformity,the method comprising the steps of (a) using a foot supporting device inconjunction with administering a botulinum toxin and (b) administeringbetween 1 and about 3,000 units of botulinum toxin type A to a buttock,thereby treating the buttock deformity. 22.-34. (canceled)